NM_177924.5:c.382+1230G>C

Variant names:

• chr8-18065990-C-G
• rs12541181
• NM_177924.5:c.382+1230G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177924.5(ASAH1):​c.382+1230G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,566 control chromosomes in the GnomAD database, including 31,840 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (31839 hom., cov: 29)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 2 publications found

Genes affected

ASAH1 (HGNC:735): (N-acylsphingosine amidohydrolase 1) This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

ASAH1 Gene-Disease associations (from GenCC):

• ASAH1-related sphingolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Farber lipogranulomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.382+1230G>C		intron_variant	Intron 5 of 13	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.382+1230G>C		intron_variant	Intron 5 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97616 AN: 151446 Hom.: 31819 Cov.: 29

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.640

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.644 AC: 97683 AN: 151564 Hom.: 31839 Cov.: 29 AF XY: 0.639 AC XY: 47285 AN XY: 73990

African (AFR) AF: 0.719 AC: 29687 AN: 41316

American (AMR) AF: 0.558 AC: 8484 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1741 AN: 3472

East Asian (EAS) AF: 0.500 AC: 2580 AN: 5160

South Asian (SAS) AF: 0.489 AC: 2349 AN: 4806

European-Finnish (FIN) AF: 0.664 AC: 6944 AN: 10456

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43808 AN: 67840

Other (OTH) AF: 0.641 AC: 1347 AN: 2100

Alfa AF: 0.647 Hom.: 3993

Bravo AF: 0.636

Asia WGS AF: 0.538 AC: 1869 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.32
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12541181; hg19: chr8-17923499;